1. Field of the Invention
The invention relates to the use of domperidone or a pharmaceutically acceptable salt thereof at low doses to prevent and/or treat a disease associated with an alteration of the immune response such as Leishmaniosis.
2. Description of the Related Art
Canine Leishmaniosis is a parasitical disease which is endemic in the countries of the Mediterranean basin where seroprevalence may reach a value of 48.4% (Alvar et al. 2004, Paradies et al 2006).
Leishmania parasites, similarly to what has also been described for other intracellular pathogenic agents, are able to survive and reproduce in the organism of infected dogs thanks to their capacity to deviate the cellular type immune response (Th1) to the humoral type immune response (Th2). Actually, clinical evolution of the disease depends mainly of the immune response developed by the animal once it has been infected. Thus an infected animal will resist the progression of the disease while it manages to maintain a predominance of the cellular immune response (Th1), with a marked production of type Th1 cytokines, such as Interferon gamma o Interleukine IL-2, which are responsible for the macrophage's activation and, through it, for their leishmanicidal potential. Conversely, when humoral response (Th2) becomes predominant, which may occur immediately after infection or after a more or less prolonged period of resistance to disease progression, the animal succumbs to the disease and starts presenting clinical signs that may even lead to death (Chamizo et al. 2005, Brachelente et al. 2005).
In dogs, resistance to the disease appears to be associated to certain balance between Th1 and Th2 responses although cellular response (Th1) seems to predominate. In species such as the mouse, disease progression or animal resistance to the disease depends on a complete polarization of the immune response towards humoral (Th2) or cellular (Th1), respectively. (Chamizo et al. 2005, Brachelente et al. 2005)
Therefore, the progression of the illness seems to be due to an alteration of the equilibrium between the cellular type immune response (Th1) and the humoral type immune response (Th2).
ES 2246142 describes the effect of Domperidone in the treatment of Leishmaniosis, administered at a dose of 2 mg/kg/day on dogs infected with L. Infantum, by means of the reestablishment of the equilibrium between the cellular type immune response (Th1) and the humoral type immune response (Th2) through an increase of prolactine blood levels. It shows that, at this dose, Domperidone is able to reduce the clinical signs of Leishmaniosis and/or to reduce the level of antibodies in infected animals.
As far as we know, there have been no attempts in the state of the art in treating or preventing Leshmaniosis in healthy or infected mammals using domperidone at a dose regime below 2 mg/kg/day. We are not aware either of any treatment or prevention method using Domperidone at a dose regime below 2 mg/kg/day during the latent phase of the illness or during secondary events or outbreaks of the illness.
In Merck 1997, it is described a recommended dose of Domperidone of 1 mg/kg/day, however, this dose regimen is restricted to a different indication, namely as an antiemetic in dogs and not for the treatment of Leshmaniosis.
The review paper about canine Leishmaniosis and its therapeutic approaches, recently published by a group of world experts in this disease (Solano-Gallego et al. 2009. Vet Parasitol, 165:1-18), states that the decrease in the antibody titre is not commonly observed until 6 months (180 days) after the onset of the treatment when serology (titration of antibodies against Leishmania) is used to monitor conventional treatments (among them Alopurinol) of the disease.
“Recent studies have demonstrated a slow and progressive decrease in IgG and IgA antibody levels which is associated with clinical improvement. Therefore we recommend repeating a quantitative serological test in the same laboratory 6 months after the initial treatment due to the relatively long half live of IgG” (page 12)
“Some dogs would present a significant decrease in antibody levels associated with clinical improvement within 6 months to 1 year of treatment while others might not have a decrease in antibody titers despite the clinical improvement” (page 12)
It would be of great interest to develop an improved use of Domperidone for the treatment of Leishmaniosis or a method of treatment of Leishmaniosis allowing to decrease the unnecessary toxicity of the active ingredient, maintaining the same efficacy of the medicament observed at the higher dose regimens described in the art and/or allowing a faster decrease of the antibody titre in the treated mammals.